JPH0363225A - Use of 5'-dioxy-5'-methylthioadeno- sine, s-adenosylmethionine and their salts in preparation of drog compouhd which stimulates hair growth of patient suffering from baldhess as wellas related drug compounds - Google Patents

Abstract

PURPOSE: To obtain a pharmaceutical composition, comprising 5'-deoxy-5'- methylthioadenosine or S-adenosylmethionine, capable of improving the nutritional functions of the scape and appendages and stimulating the hair growth of a patient suffering from the baldness. CONSTITUTION: This composition comprises 5'-deoxy-5'-methylthioadenosine(MTA), S-adenosylmethionine(SAMe) and a pharmaceutically permissible salt thereof and is suitable for oral, parenteral or topical administration. The content of the active ingredient in the composition is 50-1,600mg, preferably 600-1,200mg in the case of the oral or parenteral administration and 0.1-5wt.%, preferably 0.25-1wt.% MTA or 0.2-16wt.%, preferably 2-8wt.% SAMe in the case of the topical administration. When the MTA and SAMe are alternately used to carry out the treatment, synergistic effects are obtained.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to the use of 5'-deoxy-5'-methylthio- The present invention relates to the use of adenosine (referred to as MTA), S-adenosylmethionine (referred to as SAM) and pharmaceutically acceptable salts thereof, and related pharmaceutical compositions.

(Prior Art) Although hair does not perform any survival function for humans, it mainly plays an important psychological role in that the head of hair exhibits aesthetic factors, social factors and sexual attractiveness. Otherwise, in fact its absence produces a series of alarming and sometimes debilitating psychological effects in both men and women.

Pili and hair follicles form a functionally inseparable unit that undergoes a growth cycle in which three successive stages can be recognized during the entire lifespan (Ktigman A, M,
Author, J, Inv, D@rm, Volume 33, Page 307,
1959, Krygma 7 AoM, author, Arch, D
arm, a vol. 83, p. 175, 1961, Zaun J (Aertzl.

(See Kosmstology, Volume 8, 5 Negative, 1978).

Active growth phase (anagen) Intermediate phase (interphase) Quiescent phase (telogen) The anagen phase, with a variable duration of 3 to 5 years, is characterized by strong metabolic activity at the level of the hair root, resulting in the production of keratin and melamine and the growth of the hair. results in elongation.

The interphase stage is a transitional stage that lasts several weeks. Metabolic activity decreases and the hair roots already adjacent to the deep skin recede slightly towards the skin surface.

Telogen corresponds to a period of vesicle rest. Hair growth stops. At the end of this period of metabolic rest, which lasts several months, % new hair begins to grow at the base of the follicle, driving the telogen stage hair towards the skin surface and falling out.

If the hair cycle is fleshy, as in animal moulting, after the growth period,
I have hair loss. In contrast, in humans, hair loss is disorganized, with all growth stages present in the same hair region.

Continuous physiological renewal occurs, which ensures constant hair density, especially when the anagen phase is much longer than the telogen phase. Most hair, about 90% of healthy hair, is therefore in the anagen stage. For young adults,
Approximately ioo, ooo ~ 150,000 hairs are in an active growth stage, so on average about 35 hairs per day, 10
,000-15,000 hairs fall out each year. As a result, hair is composed of individual hairs of various types ranging from extremely fine elements with very short cycles to the thickest strands with long growth cycles. Different combinations of various proportions of these groups give the hair more or less sufficient volume, independent of the number of individual hairs present on the scalp.

However, this physiological update is a genetic meter! (make-up), subject to individual changes based on sex, H/L/M/N/4lance and season (Barman J. M., Astore ())
Astora) I, Pacoraro
V: J, Inv, Darm, 44 volumes 123
3 pages, 1965, Perman J, M., Astore I.
.

Pecoraro V: Adv, Biol, 5kin 9
Volume, 1967, Arron Prunétier/l/ (Ar
on Brunstlere) R,.

Binet O, Dompmartin-Pernot D:
Revue de MedecinA26~27.19
(See 1977).

This continuous renewal process of hair is responsible for male hair loss (and
(Blanc H,: Aer
tzlKosmstology Volume 8, Page 5, 197
8, Bieham K, D, Sbaw D, A: IFSCC Hamburg 1972). Hair loss is characterized by a shortening of anagen stages. Progression to the telogen phase is more rapid, and subsequent regrowth results in the formation of increasingly shorter hairs. It is the very fine number of hairs with very short cycles that gives alopecia-affected hair its sparse, sparse appearance. Since the telogen phase does not change its duration, there is also a relative increase in the proportion of hair in the telogen phase. A proportion of hair in the telogen stage of greater than 20% is generally considered to be a sign of alopecia (Krigv y
A, M, :J, Inv, Derm, vol. 33, p. 307, 1959, Alon Prunetière R.
Binet O0, Dompe Martin-Pernod D, : Revu
e deMadecln 426-27, 1977).

The therapeutic uses of products containing MTA and SAMe as antiviral systems, cytostatics and tumorigenic tissue transformation inhibitors are known and widely described in the literature such as British Patent No. 1,555,991. .

Therapeutic uses of this product as an anti-inflammatory, antipyretic, anti-platelet aggregation agent, and sleeping mulberry are also reported in U.S. Pat.
54° 122 and 4,373, (15) 7. , MTA and SA
For a description of the method for preparing M., reference should be made to the above-mentioned patents. However, the scalp activity of MTA and SAMs in promoting hair tC length or resisting baldness has not been described.

To date, many substances have been used for the treatment of baldness and hair loss, but none of these gave satisfactory results.

For example, the drug currently most widely used to treat alopecia, namely minoxidil (17)
A number of side effects have been reported, the most frequent of which is allergy, which is attributable to the active ingredient rather than the vehicle - sexual contact dermatitis (Fielder-Waist V, C,,'
7 Est (Waat) D, P, , Vice (Bu
ys) C, M, e Lance 74-/l/do(Ru
m5f 1ald) J, A, : Topica
lminoxidtl dose-response
effect ln allopaciaaraata,
Arch, Dermatol, 1986, 1
Volume 22, pages 180-2, Tosti (order Toa) A:
Topical m1noxitHJuseful i
n 18% off with and
rogen@ticalopacia: a 5tu
dy of 430 cmses: Dermato
logica 1986, volume 173, pages 136-8, f
・Grief (D@Grssf) H,, He:/Trickx (Hsndrickx) I,.

Dooms Gooitens
) A, :AllAl15r cntaet
dermatltls to m1noxidll
.

Contact D@rmat1t1g 1985,
Volume 13, pp. 194-5, Tosti A, Pardazzi (Bar
dazzi) F, , De Nof Dopa (De Pad)
ova) M, P, , Caboneri (Cipon@r
i) G, M, , Merino (M@1ine) M, ,
veronesi S, , Contac
t d@rmatltla to mlnoxi
dll%ContactDsrmat1tis, 1
985 Hayabusa, Vol. 13, pp. 275-6, Freindler (K
reindler) T, G, : Topica
lminoxidil in early andro
g@n@tle alop@aia.

J, Am, Aead D@rmatol 1987
16, pp. 718-24). Local symptoms such as irritation and pain have been reported from time to time. A decrease in blood pressure in normotensive patients during topical treatment with minoxidil was found by Ranchhoff and B@rgfeld.
Topicalmlnoxidll r@duc@s
bloodpr@smur@, J, Am, Ae
ad.

Dermatol 1985, vol. 12, 586~? (see page).

(Problems to be Solved by the Invention) It is an object of the present invention to substantially improve the nutritional function of the scalp and appendages and to improve hair growth, especially for patients suffering from baldness, especially for androgenetic alopecia, without any side effects. The present invention describes and claims pharmaceutical compositions that promote.

Means for Solving the Problems These objects are aimed at the preparation of a pharmaceutical composition that promotes hair growth in patients suffering from baldness, especially in patients with androgenetic alopecia.
This is achieved by using MTA, SAMe and their pharmaceutically acceptable salts.

In this regard, the present inventors have proposed that the MTA, SAMs of the present invention
, and their salts! I! ! It has been unexpectedly found that the composition is active in promoting hair growth in patients suffering from baldness, particularly those suffering from androgenetic alopecia.

This unexpected pharmacological activity, which could not be expected based on the known pharmacological activities of these products, was substantiated by numerous clinical trials. To illustrate the objects and advantages of the present invention, the results obtained in some of these clinical trials are described below.

Clinical Trial Hamilton Scale # (Hamilton 5cal
e) (Hamilt y J, B,: Am, NY
Aead, Sci, 1951, 53, 708
23 to 32 years old (average age 27.3 years) suffering from male alopecia of grade ■ crown and grade - ■ (see page 28)
Eighty patients, aged 30 to 30 years, participated in this clinical trial. The Hamilton scale for classifying baldness is shown in Figure 1.

None of the patients studied had any other local or systemic disease or had been treated with other drugs in the 2 months prior to the clinical trial.

Patients were divided into two equal groups and MTA was administered by tap at a dosage of 600 my/day in a random blinded manner.
Or they were treated with a placebo for 4 months.

The response to this treatment was assessed independently by the physician and patient in the following manner:

By appropriately translating one of the following options, the patient:
After 4 months, response to treatment with MTA or placebo was objectively assessed.

■ = No growth ■ = Minimal growth ■ = Moderate growth tV = Dense growth The experimenter objectively assessed the response to treatment with MTA t or placebo after 4 months based on the following criteria: .

■ = No growth ■ = Growth of downy hair ■ = Minimum growth of terminal hair tV = Moderate growth of terminal hair ■ = Dense growth of terminal hair Figure 2 Fi, distribution of the above four hair growth judgment choices (
%), orally administered MTA-fi or placebo (
p<0. M3 diagram illustrating the patient's subjective assessment of hair growth after 4 months of treatment with orally administered MTA or placebo (p < 0.05) illustrates the experimenter's objective evaluation of hair growth after 4 months of treatment.

Figures 2 and 3 show the four options available to the patient or the five options available to the experimenter between the two groups, the MTA-treated group and the placebo-treated group. It shows that there is a significant difference in the distribution (%) of judgment choices. In particular, there is a significantly greater frequency of 1v or V judgments given by the experimenters in the group treated with MTA than in the group receiving the wound drug.

Different dosing t of MTA or SAMs: i.e. 50 ηM
T people (10 patients), 100IIMjM100II patients), 2001#MTA (10 patients), 400
#MTA (l 0 patients), 80 (15) M'rA
(10 patients), l 2001n9MTA (10
patients), 1600 no 9 MTA (10 patients), 5
01119 SAMs (10 patients), l 00
IvS&Me (10 patients), 200 IQ SA
Ms (l 9 patients), 4001Mi SAMs (
10 patients), 800 IQ SAMs (l 0 patients), 12001n95AFV! A similar study was conducted using a pharmaceutical composition of the present invention containing 1600 mg SAMs (10 patients), and these dosages were related to evaluating hair growth. It was found that there was a significant effect on the temple parameters.

Clinical test 2 Graded on the Hamilton scale (see Figure 1)■
120 patients aged between 24 and 34 years (mean age 28.7 years) suffering from parietal and grade ■ alopecia participated in this study. None of the patients studied had any other local or systemic disease and had not been treated with other drugs for at least 2 months prior to the clinical trial. During the treatment period, patients had their hair washed once a week, all with the same delicate shampoo.

Divide into two equal groups of patients and apply 25-1 doses of MTA topically twice daily based on a random self-test method.
The patient was treated once for 4 months with Rosin9'' or a placebo.

Hair growth was assessed independently by physicians and patients after 4 months of treatment as described for clinical trial I.

Figure 4 shows the patient's subjective assessment of hair growth after 4 months of treatment with MTA Rosin or placebo, with respect to the distribution (%) of the four hair growth judgment choices as defined for the clinical trial. Illustrated.

Figure 5 shows the hair growth experiment after 4 months of treatment with MTA lotion or placebo, with respect to the distribution (%) of the five hair growth judgment choices as defined for the clinical trial (p 0.05). Illustrating an objective evaluation by a person.

From Figures 4 and 5, it can be seen that patients treated topically with MTA rosin showed a significant increase in hair growth compared to the group of patients who received a placebo (chi-square test).

Different dosages of MTA or SAMs (all expressed in % by weight relative to the solution): 0.
1% (10 patients), MTA Roshe! l/1% (10
2% (10 patients),
MTA lotion (10 patients), MTA O-'/
! 4% (10 patients), MTA 5% (10 patients), SAM lotion 0.4
% (10 patients), SAMs a-7172% (10
SAMe 4% (10 patients)
A similar clinical trial was conducted using topical pharmaceutical compositions of the present invention containing SAMe o-7478% (10 patients) to determine whether these dosages were related to the evaluation of hair growth. It was found that this had a significant effect on the meter.

In addition, MT can be administered locally, orally, and parenterally.
A synergistic effect was observed when A and SAMe were used alternately for treatment. For example, by treating a patient every other day with topically administered MTA and parenterally administered SAMs - or topically administered SAMs@
A synergistic effect is obtained by treating patients with and parenterally administered MTA.

In conclusion, it has been found that the pharmaceutical compositions of the present invention, suitable for systemic or topical administration, can significantly promote hair growth in patients suffering from baldness, especially in patients suffering from androgenetic alopecia. The n*i product acid produced from the main component of the present invention does not induce any definite side effects, and is actually toxic at therapeutic dosages regarding the administration method Magnesium Stearate Cellulose Aceto 7 Talate Diethyl Phthalate Examples One bottle of injectable form containing 8 SAMs 200119 contains the following ingredients:

SAMs 1aH1 salt P-) luenesulfonate (S
5.0Tn9 26.27n9 8.89 84In9 Mannitol-L-Lysine Sodium Hydroxide 511Ll Water for Injectable Preparation Example 9 1 Injectable Form Containing SAMe 400 Iv The bottle contains the following ingredients:

200 da 300 da 9 da SAMe 1,4-butane disulfo/acid (SAM@
(equivalent to ion 400■) 759.29 Water for injection preparation to make L-lysine sodium hydroxide 5d 323. (15) 9.6 mfI Example 10 Controlled Release Injectable Form Containing 400 ■ of 105A One bottle contains the following ingredients.

SAMs 1,4-butanedisulfo/acid salt (SAMe
Polyethylene Glycol 6000 Hydroxyethyl Cellulose L-Lysine Sodium Hydroxide 5d Water for Injectable Preparation Example 11 Controlled Release Injectable Form Containing MTA 2001n9 One bottle contains the following ingredients: .

MTA Polysorbate 80 Polyethylene Glycol 6000 Water for Injection Preparation to Make 5d Example 12 Controlled Release Herbal Medicine Containing MTA 400 ml One herbal medicine contains the following ingredients.

759.2mg 100.0In9 10.01323.0Fv 9.6dze2001119 101da100jsuMTA
400mg Human 90xyglobil methylcellulose 70% semi-synthetic dalicerite
2530 ■ Example 13 One transdermal system containing MTA 600 ■ contains the following ingredients.

MTAI, 4-butane disulfonate (equivalent to MTA 600) 820.29 Glycerin Polyvinyl Alcohol Polyvinylpyrrolidone Purified Water Example 14 Transdermal System Containing SAMs 60011 #9 One system contains the following ingredients:

1400.0II19 350.0III & 175.0■ SAMe 1 ,4-butanedisulfo/acid (SAMs
1138.89 Liquid Silicone Precipitated Silica Example 15 856.7In9 75.21n9 Lotion 100jdFi with 0.25% MTA, containing the following ingredients:

MTA sulfur rR salt (MTA 0.25, equivalent to F) Methyl p-hydroxypenzoate Globil p-hydroxybenzoate 10 A ice making for Qaff Example 16 Roshi Il/containing MTA 0.5% 1001d includes the following components.

MTAI, 4-butanedisulfo/acid acid (Equivalent to MTA O, 5, 9) Methyl p-hydroxybenzoate Glopyr p-hydroxypenshade Purified water for 1001d Example 17 Lotion containing 1% MTA 1001d includes the following components.

MTA citrate (equivalent to MTAIg) 0.21 0.15,9 0.0511 0.681i 0.15g 0.05g 1.61 Methyl p-hydroxybenzoate propyl p-hydroxybenzony 1 Purification to make 100m Water Example 18 A spray bottle/1QQd containing 0.5% MTA contains the following ingredients.

MTAI, 4-butanedisulfonate (Equivalent to 0.5g of MTA) glycerin Ethyl alcohol Methyl p-hydroxypenzoate Glopyr p-hydroxybenzoate fII to make it 100 Jlj! l! ! Water Example 19 Low scene including SAM 8% One bottle contains the following ingredients:

SAM@@1!1! Hani p-) luenesulfonate (SA
Equivalent to Ms ion 200■) Methyl p-hydroxybenzoate oval water 0.15.9 0.05N 0.68 Il 1.00! I 5.00.9 0.1511 O,05# 384.0wa 1.61v 2,5-ffij! Example 20 One bottle of Rosilon containing 08% SAM contains the following ingredients:

SAMe 1.4-findis/L/phonate
379.6In9 (equivalent to SAMs ion 200■ Methyl p-hydroxybenzony) 1
．． 6 ■ Purified water 2.5m
1

[Brief explanation of drawings]

Figure 1 shows the Hamilton scale for classifying baldness. Figure 2 shows the distribution (%) of the above four hair growth judgment choices.
) with respect to orally administered MTA or placebo (p<0
．． 05) illustrates the patient's subjective assessment of hair growth after 4 months of treatment with 05). Figure 3 shows the distribution (%) of the above five hair growth judgment choices.
) for orally administered MTA t or placebo CP<
0.05) illustrates the experimenter's objective evaluation of hair growth after 4 months of treatment. Figure 4 shows the subjective subjective opinion of patients regarding hair growth after 4 months of treatment with MTA rosin or placebo, with respect to the distribution (%) of the four hair growth judgment choices as defined for the clinical trial IK. Illustrate the evaluation. Figure 5 shows the distribution of the five hair growth judgment choices (%) (p 0.05) as defined for the clinical trial experimenter on hair growth after 4 months of treatment with 1MTA or placebo. The objective evaluation by Engraving of the drawings Figure 1 Figure 2 Figure 2.5% Placebo Figure Figure Procedure Nei City Official Book (Method) Procedural Neighborhood Official Book (Method) April 12, 1990

Claims (1)

Claims: (1) 5'-deoxy-5'-methylthioadenosine, S-adenosylmethionine and their pharmaceutical compositions in the preparation of a pharmaceutical composition for promoting hair growth in patients suffering from baldness. Use of acceptable salt. (2) Use according to claim 1, characterized in that the pharmaceutical composition is suitable for oral administration. (3) Use according to claim 1, characterized in that the pharmaceutical composition is suitable for parenteral administration. (4) The use according to claims 2 and 3, characterized in that the amount of active ingredient used is 50 to 1600 mg. (5) The amount of active ingredient used is preferably 600 to 120
Use according to claim 4, characterized in that it is 0 mg. (6) Use according to claim 1, characterized in that the pharmaceutical composition is suitable for topical application. (7) When the active ingredient is 5'-deoxy-5'-methylthio-adenosine, it is 0.1% to 5% by weight based on the solution, and when the active ingredient is S-adenosylmethionine, it is 0.1% to 5% by weight based on the solution.
7. Use according to claim 6, characterized in that it is used in an amount of 2% to 16% by weight. (8) When the active ingredient is 5'-deoxy-5'-methylthioadenosine, it is preferably 0.25% to 2% by weight of the solution, and when the active ingredient is S-adenosylmethionine, it is preferably 2% to 2% by weight of the solution. Use according to claim 7, characterized in that it is used in an amount of 8% by weight. (9) promoting hair growth in patients suffering from baldness, characterized by containing 5'-deoxy-5'-methylthioadenosine, S-adenosyl-methionine or a pharmaceutically acceptable salt thereof as an active ingredient; A pharmaceutical composition. (10) Claim 9, characterized in that it is suitable for oral administration.
Pharmaceutical compositions as described. (11) The pharmaceutical composition according to claim 9, which is suitable for parenteral administration. (12) Pharmaceutical composition according to claims 10 and 11, characterized in that the active ingredient content is 50 to 1600 mg. (13) Active ingredient content is preferably 600 to 1200 m
Pharmaceutical composition according to claim 12, characterized in that it is g. (14) Claim 9, characterized in that it is suitable for topical application.
Pharmaceutical compositions as described. (15) When the active ingredient content is 5'-deoxy-5'-methylthioadenosine, it is 0.1% by weight to 5% by weight based on the solution.
15. Pharmaceutical composition according to claim 14, characterized in that it is 0.2% to 16% by weight of the solution in the case of S-adenosylmethionine. (16) When the active ingredient content is 5'-deoxy-5'-methylthioadenosine, preferably 0.2
Pharmaceutical composition according to claim 15, characterized in that it is 5% to 2% by weight, and in the case of S-adenosylmethionine, 2% to 8% by weight, based on the solution. (17) A method for treating baldness by administering a pharmaceutical composition having 5'-deoxy-5'-methylthioadenosine, S-adenosylmethionine, or a pharmaceutically acceptable salt thereof as an active ingredient. (18) The therapeutic method according to claim 17, wherein the administration is oral or parenteral. (19) The therapeutic method according to claim 18, characterized in that the active ingredient content is 50 to 1600 mg. (20) Active ingredient content is preferably 600 to 1200
The therapeutic method according to claim 19, characterized in that the amount is mg. (21) Claim 1, characterized in that the administration is local.
7. The treatment method described in 7. (22) When the active ingredient content is 5'-deoxy-5'-methylthioadenosine, it is 0.1% by weight to 5% by weight based on the solution.
22. The method of treatment according to claim 21, characterized in that it is 0.2% to 16% by weight of the solution in the case of S-adenosylmethionine. (23) When the active ingredient content is 5'-deoxy-5'-methylthioadenosine, preferably 0.2
23. The method of treatment according to claim 22, characterized in that the amount is 5% to 2% by weight, and in the case of S-adenosylmethionine, 2% to 8% by weight of the solution.